Construction of complex memories via parallel distributed cortical-subcortical iterative integration.

The construction of complex engrams requires hippocampal-cortical interactions. These include both direct interactions and ones via often-overlooked subcortical loops. Here, we review the anatomical organization of a hierarchy of parallel 'Papez' loops through the hypothalamus that are homologous in mammals from rats to humans. These hypothalamic loops supplement direct hippocampal-cortical connections with iterative reprocessing paced by theta rhythmicity. We couple existing anatomy and lesion data with theory to propose that recirculation in these loops progressively enhances desired connections, while reducing interference from competing external goals and internal associations. This increases the signal-to-noise ratio in the distributed engrams (neocortical and cerebellar) necessary for complex learning and memory. The hypothalamic nodes provide key motivational input for engram enhancement during consolidation.

Evidence for two distinct thalamocortical circuits in retrosplenial cortex.

Retrosplenial cortex (RSC) lies at the interface between sensory and cognitive networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and thalamic connectivity, as a step towards understanding their functions. The gRSC is more closely connected to the hippocampal formation, in which theta-band local field potential oscillations are prominent. We, therefore, compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to test for differential inputs to RSC from the anteroventral thalamus (AV). We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). Specifically: (1) as a whole AV projects more strongly to gRSC; (2) AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC, (3) the gRSC projection is layer-specific: AVDM targets specifically gRSC superficial layers. These same AV projections are topographically organized with ventral AV neurons innervating rostral RSC and dorsal AV neurons innervating caudal RSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC, or both.

Dentate Nucleus: Connectivity-Based Anatomic Parcellation Based on Superior Cerebellar Peduncle Projections.

OBJECTIVE: Projections from the dentate nucleus (DN) follow a certain organized course to upper levels. Crossing and noncrossing fibers of the dentatorubrothalamic (DRT) tract terminate in the red nucleus and thalamus and have various connections throughout the cerebral cortex. We aimed to establish the microsurgical anatomy of the DN in relation to its efferent connections to complement the increased recognition of its surgical importance and also to provide an insight into the network-associated symptoms related to lesions and microsurgery in and around the region. METHODS: The cerebellum, DN, and superior cerebellar peduncle (SCP) en route to red nucleus were examined through fiber dissections from the anterior, posterior, and lateral sides to define the connections of the DN and its relationships with adjacent neural structures. RESULTS: The DN was anatomically divided into 4 areas based on its relation to the SCP; the lateral major, lateral anterosuperior, posteromedial, and anteromedial compartments. Most of the fibers originating from the lateral compartments were involved in the decussation of the SCP. The ventral fibers originating from the lateral anterosuperior compartment were exclusively involved in the decussation. The fibers from the posteromedial compartment ascended ipsilaterally and decussated, whereas most anteromedial fibers ascended ipsilaterally and did not participate in the decussation. CONCLUSIONS: Clarifying the anatomofunctional organization of the DN in relation to the SCP could improve microneurosurgical results by reducing the complication rates during infratentorial surgery in and around the nucleus. The proposed compartmentalization would be a major step forward in this effort.

Morphological Analysis of the Hindbrain Glucose Sensor-Hypothalamic Neural Pathway Activated by Hindbrain Glucoprivation.

Lowered glucose availability, sensed by the hindbrain, has been suggested to enhance gluconeogenesis and food intake as well as suppress reproductive function. In fact, our previous histological and in vitro studies suggest that hindbrain ependymal cells function as a glucose sensor. The present study aimed to clarify the hindbrain glucose sensor-hypothalamic neural pathway activated in response to hindbrain glucoprivation to mediate counterregulatory physiological responses. Administration of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, into the fourth ventricle (4V) of male rats for 0.5 hour induced messenger RNA (mRNA) expression of c-fos, a marker for cellular activation, in ependymal cells in the 4V, but not in the lateral ventricle, the third ventricle or the central canal without a significant change in blood glucose and testosterone levels. Administration of 2DG into the 4V for 1 hour significantly increased blood glucose levels, food intake, and decreased blood testosterone levels. Simultaneously, the expression of c-Fos protein was detected in the 4V ependymal cells; dopamine ß-hydroxylase-immunoreactive cells in the C1, C2, and A6 regions; neuropeptide Y (NPY) mRNA-positive cells in the C2; corticotropin-releasing hormone (CRH) mRNA-positive cells in the hypothalamic paraventricular nucleus (PVN); and NPY mRNA-positive cells in the arcuate nucleus (ARC). Taken together, these results suggest that lowered glucose availability, sensed by 4V ependymal cells, activates hindbrain catecholaminergic and/or NPY neurons followed by CRH neurons in the PVN and NPY neurons in the ARC, thereby leading to counterregulatory responses, such as an enhancement of gluconeogenesis, increased food intake, and suppression of sex steroid secretion.

The synaptic inputs and thalamic projections of two classes of layer 6 corticothalamic neurons in primary somatosensory cortex of the mouse.

Although corticothalamic neurons (CThNs) represent the largest source of synaptic input to thalamic neurons, their role in regulating thalamocortical interactions remains incompletely understood. CThNs in sensory cortex have historically been divided into two types, those with cell bodies in Layer 6 (L6) that project back to primary sensory thalamic nuclei and those with cell bodies in Layer 5 (L5) that project to higher-order thalamic nuclei and subcortical structures. Recently, diversity among L6 CThNs has increasingly been appreciated. In the rodent somatosensory cortex, two major classes of L6 CThNs have been identified: one projecting to the ventral posterior medial nucleus (VPM-only L6 CThNs) and one projecting to both VPM and the posterior medial nucleus (VPM/POm L6 CThNs). Using rabies-based tracing methods in mice, we asked whether these L6 CThN populations integrate similar synaptic inputs. We found that both types of L6 CThNs received local input from somatosensory cortex and thalamic input from VPM and POm. However, VPM/POm L6 CThNs received significantly more input from a number of additional cortical areas, higher order thalamic nuclei, and subcortical structures. We also found that the two types of L6 CThNs target different functional regions within the thalamic reticular nucleus (TRN). Together, our results indicate that these two types of L6 CThNs represent distinct information streams in the somatosensory cortex and suggest that VPM-only L6 CThNs regulate, via their more restricted circuits, sensory responses related to a cortical column while VPM/POm L6 CThNs, which are integrated into more widespread POm-related circuits, relay contextual information.

Mesoscale hierarchical organization of primary somatosensory cortex captured by resting-state-fMRI in humans.

The primary somatosensory cortex (S1) plays a key role in the processing and integration of afferent somatosensory inputs along an anterior-to-posterior axis, contributing towards necessary human function. It is believed that anatomical connectivity can be used to probe hierarchical organization, however direct characterization of this principle in-vivo within humans remains elusive. Here, we use resting-state functional connectivity as a complement to anatomical connectivity to investigate topographical principles of human S1. We employ a novel approach to examine mesoscopic variations of functional connectivity, and demonstrate a topographic organisation spanning the region's hierarchical axis that strongly correlates with underlying microstructure while tracing along architectonic Brodmann areas. Our findings characterize anatomical hierarchy of S1 as a 'continuous spectrum' with evidence supporting a functional boundary between areas 3b and 1. The identification of this topography bridges the gap between structure and connectivity, and may be used to help further current understanding of sensorimotor deficits.

Microsurgical anatomy of the amygdaloid body and its connections.

The amygdaloid body is a limbic nuclear complex characterized by connections with the thalamus, the brainstem and the neocortex. The recent advances in functional neurosurgery regarding the treatment of refractory epilepsy and several neuropsychiatric disorders renewed the interest in the study of its functional Neuroanatomy. In this scenario, we felt that a morphological study focused on the amygdaloid body and its connections could improve the understanding of the possible  implications in functional neurosurgery. With this purpose we performed a morfological study using nine formalin-fixed human hemispheres dissected under microscopic magnification by using the fiber dissection technique originally described by Klingler. In our results the  amygdaloid body presents two divergent projection systems named dorsal and ventral amygdalofugal pathways connecting the nuclear complex with the septum and the hypothalamus. Furthermore, the amygdaloid body is connected with the hippocampus through the amygdalo-hippocampal bundle, with the anterolateral temporal cortex through the amygdalo-temporalis fascicle, the anterior commissure and the temporo-pulvinar bundle of Arnold, with the insular cortex through the lateral olfactory stria, with the ambiens gyrus, the para-hippocampal gyrus and the basal forebrain through the cingulum, and with the frontal cortex through the uncinate fascicle. Finally, the amygdaloid body is connected with the brainstem through the medial forebrain bundle. Our description of the topographic anatomy of the amygdaloid body and its connections, hopefully represents a useful tool for clinicians and scientists, both in the scope of application and speculation.

Projections from the dorsomedial division of the bed nucleus of the stria terminalis to hypothalamic nuclei in the mouse.

As stressful environment is a potent modulator of feeding, we seek in the present work to decipher the neuroanatomical basis for an interplay between stress and feeding behaviors. For this, we combined anterograde and retrograde tracing with immunohistochemical approaches to investigate the patterns of projections between the dorsomedial division of the bed nucleus of the stria terminalis (BNST), well connected to the amygdala, and hypothalamic structures such as the paraventricular (PVH) and dorsomedial (DMH), the arcuate (ARH) nuclei and the lateral hypothalamic areas (LHA) known to control feeding and motivated behaviors. We particularly focused our study on afferences to proopiomelanocortin (POMC), agouti-related peptide (AgRP), melanin-concentrating-hormone (MCH) and orexin (ORX) neurons characteristics of the ARH and the LHA, respectively. We found light to intense innervation of all these hypothalamic nuclei. We particularly showed an innervation of POMC, AgRP, MCH and ORX neurons by the dorsomedial and dorsolateral divisions of the BNST. Therefore, these results lay the foundation for a better understanding of the neuroanatomical basis of the stress-related feeding behaviors.

Revisiting Forel Field Surgery.

BACKGROUND: Lesioning the Forel field or the subthalamic region is considered a possible treatment for tremoric patients with Parkinson disease, essential tremor, and other diseases. This surgical treatment was performed in the 1960s to 1970s and was an alternative to thalamotomy. Recently, there has been increasing interest in the reappraisal of stimulating and/or lesioning these targets, partly as a result of innovations in imaging and noninvasive ablative technologies, such as magnetic resonance-guided focused ultrasonography. OBJECTIVE: We wanted to perform a thorough review of the subthalamic region, both from an anatomic and a surgical standpoint, to offer a comprehensive and updated analysis of the techniques and results reported for patients with tremor treated with different techniques. METHODS: We performed a systematic review of the literature, gathering articles that included patients who underwent ablative or stimulation surgical techniques, targeting the pallidothalamic pathways (pallidothalamic tractotomy), cerebellothalamic pathway (cerebellothalamic tractotomy), or subthalamic area. RESULTS: Pallidothalamic tractotomy consists of a reduced area that includes pallidofugal pathways. It may be considered an interesting target, given the benefit/risk ratio and the clinical effect, which, compared with pallidotomy, involves a lower risk of injury or involvement of vital structures such as the internal capsule or optic tract. Cerebellothalamic tractotomy and/or posterior subthalamic area are other alternative targets to thalamic stimulation or ablative surgery. CONCLUSIONS: Based on the significant breakthrough that magnetic resonance-guided focused ultrasonography has meant in the neurosurgical world, some classic targets such as the pallidothalamic tract, Forel field, and posterior subthalamic area may be reconsidered as surgical alternatives for patients with movement disorders.

Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse.

The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.

Topographic organization of the human subcortex unveiled with functional connectivity gradients.

Brain atlases are fundamental to understanding the topographic organization of the human brain, yet many contemporary human atlases cover only the cerebral cortex, leaving the subcortex a terra incognita. We use functional MRI (fMRI) to map the complex topographic organization of the human subcortex, revealing large-scale connectivity gradients and new areal boundaries. We unveil four scales of subcortical organization that recapitulate well-known anatomical nuclei at the coarsest scale and delineate 27 new bilateral regions at the finest. Ultrahigh field strength fMRI corroborates and extends this organizational structure, enabling the delineation of finer subdivisions of the hippocampus and the amygdala, while task-evoked fMRI reveals a subtle subcortical reorganization in response to changing cognitive demands. A new subcortical atlas is delineated, personalized to represent individual differences and used to uncover reproducible brain-behavior relationships. Linking cortical networks to subcortical regions recapitulates a task-positive to task-negative axis. This new atlas enables holistic connectome mapping and characterization of cortico-subcortical connectivity.

Mapping tracts in the human subthalamic area by 11.7T ex vivo diffusion tensor imaging.

The cortico-basal ganglia-thalamo-cortical feedback loops that consist of distinct white matter pathways are important for understanding in vivo imaging studies of functional and anatomical connectivity, and for localizing subthalamic white matter structures in surgical approaches for movement disorders, such as Parkinson's disease. Connectomic analysis in animals has identified fiber connections between the basal ganglia and thalamus, which pass through the fields of Forel, where other fiber pathways related to motor, sensory, and cognitive functions co-exist. We now report these pathways in the human brain on ex vivo mesoscopic (250 µm) diffusion tensor imaging and on tractography. The locations of the tracts were identified relative to the adjacent gray matter structures, such as the internal and external segments of the globus pallidus; the zona incerta; the subthalamic nucleus; the substantia nigra pars reticulata and compacta; and the thalamus. The connectome atlas of the human subthalamic region may serve as a resource for imaging studies and for neurosurgical planning.

A Whole-brain Map of Long-range Inputs to GABAergic Interneurons in the Mouse Caudal Forelimb Area.

The caudal forelimb area (CFA) of the mouse cortex is essential in many forelimb movements, and diverse types of GABAergic interneuron in the CFA are distinct in the mediation of cortical inhibition in motor information processing. However, their long-range inputs remain unclear. In the present study, we combined the monosynaptic rabies virus system with Cre driver mouse lines to generate a whole-brain map of the inputs to three major inhibitory interneuron types in the CFA. We discovered that each type was innervated by the same upstream areas, but there were quantitative differences in the inputs from the cortex, thalamus, and pallidum. Comparing the locations of the interneurons in two sub-regions of the CFA, we discovered that their long-range inputs were remarkably different in distribution and proportion. This whole-brain mapping indicates the existence of parallel pathway organization in the forelimb subnetwork and provides insight into the inhibitory processes in forelimb movement to reveal the structural architecture underlying the functions of the CFA.

Fiber dissection and 3-tesla diffusion tensor tractography of the superior cerebellar peduncle in the human brain: emphasize on the cerebello-hypthalamic fibers.

Experimental studies in various species using tract-tracing techniques showed clear evidence of the presence of cerebello-hypothalamic projections. However, these connections were not clearly described in humans. In the present study we aimed to describe the direct cerebello-hypothalamic connections within the superior cerebellar peduncle (SCP) using fiber dissection techniques on cadaveric brains and diffusion tensor tractography (DTI) in healthy adults. Fiber dissection was performed in a stepwise manner from lateral to medial on 6 cerebral hemispheres. The gray matter was decorticate and fiber tracts were revealed. The SCP was exposed and the fibers were traced distally using wooden spatulas. The MRI examinations were performed in seven cases using 3-tesla 3T unit. The direct cerebello-hyothalamic pathways were exposed using high-spatial-resolution DTI. The present study using both fiber dissection and DTI in adult human showed direct cerebello-hypothalamic fibers within the SCP. The SCP fibers course anterolateral to the cerebral aqueduct reaching the level of the red nucleus of the midbrain. The majority of the fibers crosses over and reached the contralateral diencephalic structures and some of these fibers terminated at the contralateral anterior hypothalamic area. Some of the uncrossed SCP fibers reached the ipsilateral diencephalic structures and terminated at the ipsilateral posterior hypothalamic area. We further reported the close relationship of the SCP with the MCP, lateral lemniscus, red nucleus and substantia nigra. In the DTI evaluations of the SCP we exposed unilateral left cerebello-hypothalamic fibers in five cases and bilateral cerebello-hypothalamic fibers in two cases. The present study demonstrates the direct cerebello-hypothalamic connections within the SCP for the first time using fiber dissection and DTI technique in the human brain. The detailed knowledge of the cerebello-hypothalamic fibers can outline the unexplained deficit that may occur during regional surgery.

The white matter architecture underlying semantic processing: A systematic review.

From a holistic point of view, semantic processes are subserved by large-scale subcortico-cortical networks. The dynamic routing of information between grey matter structures depends on the integrity of subcortical white matter pathways. Nonetheless, controversy remains on which of these pathways support semantic processing. Therefore, a systematic review of the literature was performed with a focus on anatomo-functional correlations obtained from direct electrostimulation during awake tumor surgery, and conducted between diffusion tensor imaging metrics and behavioral semantic performance in healthy and aphasic individuals. The 43 included studies suggest that the left inferior fronto-occipital fasciculus contributes to the essential connectivity that allows semantic processing. However, it remains uncertain whether its contributive role is limited to the organization of semantic knowledge or extends to the level of semantic control. Moreover, the functionality of the left uncinate fasciculus, inferior longitudinal fasciculus and the posterior segment of the indirect arcuate fasciculus in semantic processing has to be confirmed by future research.

Whole course of pallidothalamic tracts identified on the sectioned images and surface models.

The anatomy of the pallidothalamic tracts, including the ansa lenticularis, lenticular fasciculus, and thalamic fasciculus (field H1 of Forel), should be elucidated by neurosurgeons and neuroscientists who study deep brain stimulation. In this study, serially sectioned images of a human cadaver head were employed to overcome the limitations of existing methods to observe the pallidothalamic tracts. Owing to the high resolution and real color of the sectioned images, 28 structures, including the pallidothalamic tracts and mammillothalamic fasciculus, were identified. The structures were segmented and made into surface models, which are helpful in improving the stereoscopic understanding. Observing the sectioned images and surface models may help in understanding the detailed anatomy of the pallidothalamic tracts. The new findings, such as the spatial relationship of the tracts, were summarized in a schematic figure. Moreover, to elucidate the anatomical structures along the course of deep brain stimulation, virtual electrodes were inserted into the surface models. The sectioned images and surface models of this study are expected to enhance the understanding of the pallidothalamic tract anatomy. A portable document format file containing the surface models and the sectioned images can be freely downloaded from the authors' homepage. Clin. Anat. 32:66-76, 2019. © 2019 Wiley Periodicals, Inc.

Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex.

Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely innervates L1 and L5A. We optogenetically stimulated VPM or POm axons, and recorded evoked excitatory postsynaptic potentials (EPSPs) in different cell-types across cortical layers in wS1. We found that excitatory neurons and parvalbumin-expressing inhibitory neurons received the largest EPSPs, dominated by VPM input to L4 and POm input to L5A. In contrast, somatostatin-expressing inhibitory neurons received very little input from either pathway in any layer. Vasoactive intestinal peptide-expressing inhibitory neurons received an intermediate level of excitatory input with less apparent layer-specificity. Our data help understand how wS1 neocortical microcircuits might process and integrate sensory and higher-order inputs.

Hierarchical organization of cortical and thalamic connectivity.

The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource1, involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network.

A repeated molecular architecture across thalamic pathways.

The thalamus is the central communication hub of the forebrain and provides the cerebral cortex with inputs from sensory organs, subcortical systems and the cortex itself. Multiple thalamic regions send convergent information to each cortical region, but the organizational logic of thalamic projections has remained elusive. Through comprehensive transcriptional analyses of retrogradely labeled thalamic neurons in adult mice, we identify three major profiles of thalamic pathways. These profiles exist along a continuum that is repeated across all major projection systems, such as those for vision, motor control and cognition. The largest component of gene expression variation in the mouse thalamus is topographically organized, with features conserved in humans. Transcriptional differences between these thalamic neuronal identities are tied to cellular features that are critical for function, such as axonal morphology and membrane properties. Molecular profiling therefore reveals covariation in the properties of thalamic pathways serving all major input modalities and output targets, thus establishing a molecular framework for understanding the thalamus.

The network organization of rat intrathalamic macroconnections and a comparison with other forebrain divisions.

The thalamus is 1 of 4 major divisions of the forebrain and is usually subdivided into epithalamus, dorsal thalamus, and ventral thalamus. The 39 gray matter regions comprising the large dorsal thalamus project topographically to the cerebral cortex, whereas the much smaller epithalamus (2 regions) and ventral thalamus (5 regions) characteristically project subcortically. Before analyzing extrinsic inputs and outputs of the thalamus, here, the intrinsic connections among all 46 gray matter regions of the rat thalamus on each side of the brain were expertly collated and subjected to network analysis. Experimental axonal pathway-tracing evidence was found in the neuroanatomical literature for the presence or absence of 99% of 2,070 possible ipsilateral connections and 97% of 2,116 possible contralateral connections; the connection density of ipsilateral connections was 17%, and that of contralateral connections 5%. One hub, the reticular thalamic nucleus (of the ventral thalamus), was found in this network, whereas no high-degree rich club or clear small-world features were detected. The reticular thalamic nucleus was found to be primarily responsible for conferring the property of complete connectedness to the intrathalamic network in the sense that there is, at least, one path of finite length between any 2 regions or nodes in the network. Direct comparison with previous investigations using the same methodology shows that each division of the forebrain (cerebral cortex, cerebral nuclei, thalamus, hypothalamus) has distinct intrinsic network topological organization. A future goal is to analyze the network organization of connections within and among these 4 divisions of the forebrain.